Selenium (Se) has shown cancer preventive activity in a long-term NCI sponsored human intervention trial in which a daily supplement of 200 micrograms was given to a population with a daily intake of less than 100 micrograms, similar to that of much of the U.S. population. Only limited information is available on the baseline (unsupplemented) metabolism of either inorganic or organic Se in humans, and no information is available on changes in metabolism of either form that would likely result from a three-fold increase in intake. A study is in progress to provide information on the pharmacokinetics of Se in its prototype forms: sodium selenite and selenomethionine (SeMet). This information is necessary for the determination of time and manner of administration in future human trials. Integrated kinetic models are being used to interpret the study data. Various body pools have been hypothesized and rates of exchange between them estimated, as well as residence times. The models indicate important kinetic differences between selenite and selenomethionine. Alternative models were used to investigate one of the most important differences, the recirculation of the organic, but not the inorganic form. The models have been modified and combined into a single model to better simulate dietary intake of selenium. A refinement in the adjustment of the analytical data resulted in slightly different values for the data on which the models are based. These data reflect only tracer in the dose. The selenite model has been modified to exclude body stores of the tracer, and the data are being reentered and refitted; the existing model provides adequate fits to the modified data. The importance of kinetic studies to prevention trials has been investigated, and the results presented in a national meeting. In collaboration with the Cancer Prevention Studies Branch; the Beltsville Human Nutrition Research Center, USDA; and Cornell University, a second kinetics study to last three years has been designed, which will include 1) a 6-month baseline study, in which data on both inorganic and organic Se will be collected to permit refinement of the above models; 2) a 2-year period in which subjects will be supplemented with 200 micrograms/d of SeMet; and 3) a second 6-month kinetics study. Possible changes in metabolism, in the distribution of plasma seleno-proteins, and in the composition of the colonic microbial community arising from long-term selenium supplementation will be investigated. A study protocol has been prepared and reviewed by an outside group of experts in the areas of Se research, compartmental modeling, and clinical trials, as by the NCI IRB and modified in accordance with their comments. As this protocol will likely accompany a request for an IND for selenomethionine from the FDA, it is being reviewed for this purpose.